The opioid receptor family, consisting of μ-, δ- and κ- receptors, is a member of the rhodopsin subfamily in the superfamily of G-protein coupled receptors (GPCRs). These receptors share extensive structural and sequence homology (˜60% amino acid identity) but recognise structurally diverse ligands comprising exogenous opiates, endogenous peptides and synthetic peptidic and non-peptidic ligands (Waldhoer et al., Annu. Rev. Biochem (2004) 73: 953-990). Opiates e.g. morphine and synthetic opioids e.g. fentanyl, acting through their activity at the μ-opioid receptor are some of the most potent analgesic drugs for moderate to severe pain conditions. However, for chronic pain conditions, their widespread use is limited by side effects such as constipation, respiratory depression, nausea, sedation, physical dependence and the potential for addiction. Opioid receptors are widely expressed in the central nervous system (CNS) and periphery of many species including man. Opioid receptors have been localised on peripheral processes of sensory neurones in animals and humans (Stein et al., 2003). Most opiates and opioids mediate their analgesic effects via peripheral, spinal and supraspinal receptors. However recent preclinical and clinical studies, using either local administration or compounds with special physicochemical and/or pharmacokinetic properties to restrict their action to the periphery, suggest that analgesia can be achieved via peripheral μ-opioid receptors (MORs) alone (Bileviciute-Ljungar et al., J. Pharmacol. Exp. Ther. (2006) 317: 220-227; Gordon et al., Drug disc. Today: Ther. Strat. (2009) in press; He et al., J. Pain (2009) 10: 369-379; Koppert et al., Anesth Analg (1999) 88: 117-122; Oeltjenbruns and Schafer, Curr. Pain Headache Reports 2005; 9: 36-44; Stein et al., Nat. Med. (2003) 9: 1003-1008; Stein and Lang, Curr. Opin. Pharmacol. (2009) 9: 1-6; Wenk et al., J. Neurophysiol. (2006) 95: 2083-2097). In general, efficacy is achieved under conditions of ongoing inflammation. This is consistent with the observation of increased primary afferent MORs in inflammatory models of pain and with the expression of MORs on inflammation-attracted immune cells. Frakefamide, a synthetic μ-opioid receptor agonist demonstrated efficacy in a dental pain study (Becktor et al., abstract from 2002 World Congress on Pain) at doses that did not elicit respiratory depression (Österlund Modalen et al., abstract from 2002 World Congress on Pain; Österlund Modalen et al., 2005; Anesth Analg, 100: 713-717). Synthetic compounds acting specifically through peripheral μ-opioid receptors provide the potential to effectively manage pain without the centrally-mediated adverse effects of drugs like morphine, e.g. Current Pharmaceutical Design, 2004 (10), 743-757; Ther Clin Risk Manag. 2005 December; 1(4): 279-297.
Replacement of Tyrosine with dimethylTyrosine is described in Bioorganic & Medicinal Chemistry Letters 17 (2007) 2043-2046, European Journal of Pharmacology, Volume 302, Issues 1-3, 29 Apr. 1996, Pages 37-42.
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There is a need to provide new opioid receptor agonists that are good drug candidates. In particular, compounds should preferably bind potently to the μ-opioid receptor whilst showing little affinity for other receptors and show functional activity as μ-opioid receptor agonists. They should preferably be well absorbed from the gastrointestinal tract, and/or be injectable directly into the bloodstream, muscle, or subcutaneously, and/or be metabolically stable and possess favourable pharmacokinetic properties. When targeted against receptors in the central nervous system they should cross the blood brain barrier freely and when targeted selectively against receptors in the peripheral nervous system they should not cross the blood brain barrier. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated.